4-fluorosalicyclic acid derivative and process for production thereof

ABSTRACT

The present invention provides a 4-fluorosalicylic acid derivative represented by the following general formula (1): ##STR1## (wherein X 1 , X 2  and X 3  are each independently a hydrogen atom or a halogen atom with a proviso that there is no case in which all of X 1 , X 2  and X 3  are hydrogen atoms or fluorine atoms simultaneously); and a process for producing the above 4-fluoro-salicylic acid derivative. 
     The 4-fluorosalicylic acid derivative of the present invention is a novel compound not described in any literature and is very suitable as a raw material for production of a 3-fluorophenol derivative (the 3-fluorophenol derivative is very useful as an intermediate for liquid crystal, recording material, medicine and agricultural chemical) because the 4-fluorosalicylic acid derivative can be easily converted to the 3-fluorophenol derivative.

TECHNICAL FIELD

The present invention relates to a novel 4-fluorosalicylic acidderivative which can be easily converted to a 3-fluorophenol derivativevery useful as an intermediate for liquid crystal, recording material,medicine, agricultural chemical, etc., as well as to a process forproduction of said 4-fluorosalicylic acid derivative.

BACKGROUND ART

The 4-fluorosalicylic acid derivative of the present invention is anovel compound which has been unknown and which is not described in anyliterature. It has been also unknown that the 4-fluorosalicylic acidderivative can become a useful raw material for producing a3-fluorophenol derivative useful as an intermediate for liquid crystal[refer to Japanese Patent Application Kokai (Laid-Open) No. 291899/1995and Japanese Patent Application Kokai (Laid-Open) No. 10847/1995],recording material [refer to Japanese Patent Application Kokai(Laid-Open) No. 264587/1991], agricultural chemical [refer to JapanesePatent Application Kokai (Laid-Open) No. 345740/1994], medicine [referto Japanese Patent Application Kokai (Laid-Open) No. 309837/1995], etc.

The objects of the present invention are to provide a novel4-fluorosalicylic acid derivative which can be easily converted to a3-fluorophenol derivative useful as mentioned above, and a process forproducing the 4-fluorosalicylic acid derivative.

The present inventors made a study in order to achieve the aboveobjects. As a result, the present inventors found out that a useful3-fluorophenol derivative can be easily produced by decarboxylation of a4-fluorosalicylic acid derivative and that the 4-fluorosalicylic acidderivative used as a raw material in the decarboxylation is a novelcompound not described in any literature and is useful not only as anintermediate in production of the 3-fluorophenol derivative but also inproduction of liquid crystals, etc. The present invention has beencompleted based on the above finding.

DISCLOSURE OF THE INVENTION

The present invention provides a 4-fluorosalicylic acid derivativerepresented by the following general formula (1): ##STR2## (wherein X¹,X² and X³ are each independently a hydrogen atom or a halogen atom witha proviso that there is no case in which all of X¹, X² and X³ arehydrogen atoms or fluorine atoms simultaneously).

The present invention also provides a process for producing a4-fluorosalicylic acid derivative represented by the following generalformula (1): ##STR3## (wherein X¹, X² and X³ are each independently ahydrogen atom or a halogen atom with a proviso that there is no case inwhich all of X¹, X² and X³ are hydrogen atoms or fluorine atomssimultaneously), which process comprises reacting a 2,4-difluorobenzoicacid derivative represented by the following general formula (4):##STR4## (wherein X¹, X² and X³ are each independently a hydrogen atomor a halogen atom with a proviso that there is no case in which all ofX¹, X² and X³ are hydrogen atoms or fluorine atoms simultaneously) withan alkali metal hydroxide in at least one solvent selected from thegroup consisting of a compound represented by the following generalformula (2): ##STR5## [wherein A is a group --CH₂ -- or a group --NR'--(wherein R' is a lower alkyl group); R is a lower alkyl group; W is alower alkyl group; X is a hydrogen atom or a lower alkyl group when A isa group --CH₂ --, and is a lower alkyl group when A is a group --NR'--;W and X may combine with each other to form a lower alkylene group andbecome a 5- to 7-membered ring together with --N--C--A--] and a compoundrepresented by the following general formula (3):

    Y--Q--Z                                                    (3)

(wherein Q is a group --SO-- or a group --SO₂ --; Y and Z are eachindependently a lower alkyl group; Y and Z may combine with each otherto form a lower alkylene group and become a 4- to 6-membered ringtogether with a group --SO-- or a group --SO₂ --).

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is hereinafter described in detail.

The compound of the present invention is a 4-fluorosalicylic acidderivative represented by the above-mentioned general formula (1). Inthe general formula (1), the substituents represented by X¹, X² and X³are each independently a hydrogen atom or a halogen atom with a provisothat there is no case in which all of X¹, X² and X³ are hydrogen atomsor fluorine atoms simultaneously. Here, the halogen atoms refer to afluorine atom, a chlorine atom and a bromine atom. The compoundrepresented by the general formula (1) can be exemplified by3,4-difluorosalicylic acid, 5-chloro-4-fluorosalicylic acid,3,5-dichloro-4-fluorosalicylic acid, 4,6-difluorosalicylic acid,3,4,5-trifluorosalicylic acid and 4,5-difluorosalicylic acid.

The compound of the present invention can be produced, for example, bythe following process of the present invention.

That is, a 2,4-difluorobenzoic acid derivative represented by thefollowing general formula (4): ##STR6## (wherein X¹, X² and X³ are eachindependently a hydrogen atom or a halogen atom with a proviso thatthere is no case in which all of X¹, X² and X³ are hydrogen atoms orfluorine atoms simultaneously) is reacted with an alkali metal hydroxidein at least one solvent selected from the group consisting of a compoundrepresented by the following general formula (2): ##STR7## [wherein A isa group --CH₂ -- or a group --NR'-- (wherein R' is a lower alkyl group);R is a lower alkyl group; W is a lower alkyl group; X is a hydrogen atomor a lower alkyl group when A is a group --CH₂ --, and is a lower alkylgroup when A is a group --NR'--; W and X may combine with each other toform a lower alkylene group and become a 5- to 7-membered ring togetherwith --N--C--A--] and a compound represented by the following generalformula (3):

    Y--Q--Z                                                    (3)

(wherein Q is a group --SO-- or a group --SO₂ --; Y and Z are eachindependently a lower alkyl group; Y and Z may combine with each otherto form a lower alkylene group and become a 4- to 6-membered ringtogether with a group --SO-- or a group --SO₂ --). After the completionof the reaction, the reaction mixture is subjected to an ordinarypost-treatment such as precipitation by acidification or the like,whereby the present invention compound can be isolated.

The compound used as a solvent in the process of the present inventionis a compound represented by the general formula (2) or a compoundrepresented by the general formula (3). In the general formula (2), thelower alkyl groups represented by the substituents R, R', W and X (X maybe a hydrogen atom) are each independently an alkyl group having 1 to 4carbon atoms, such as methyl group, ethyl group, n-propyl group,isopropyl group, n-butyl group, isobutyl group or the like; and thelower alkylene group formed when the substituents W and X combine witheach other, is an alkylene group having 2 to 4 carbon atoms, such asethylene group, trimethylene group, tetramethylene group or the like.

Also in the general formula (3), the lower alkyl groups represented bythe substituents Y and Z are each independently an alkyl group having 1to 4 carbon atoms, such as methyl group, ethyl group, n-propyl group,isopropyl group, n-butyl group, isobutyl group or the like; and thelower alkylene group formed when the substituents Y and Z combine witheach other, is an alkylene group having 3 to 5 carbon atoms, such astrimethylene group, tetramethylene group, pentamethylene group or thelike.

Of the compounds represented by the general formula (2) or (3), thosepreferable as the solvent used in the process of the present inventionare 1,3-dimethyl-2-imidazolidinone, 1-methyl-2-pyrrolidone,1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, dimethyl sulfoxide,N,N-diethylacetamide, 1,1,3,3-tetramethylurea, tetramethylenesulfone anddimethylsulfone.

The amount of the solvent used can be at least an amount enablingstirring during the reaction, but is usually 0.1 to 6 litter, preferably0.3-3 litter per mole of the 2,4-difluorobenzoic acid derivativerepresented by the general formula (4).

The alkali metal hydroxide used in the process of the present inventioncan be exemplified by lithium hydroxide, sodium hydroxide and potassiumhydroxide. Of these, sodium hydroxide and lithium hydroxide arepreferred.

The amount of the alkali metal hydroxide used can be 2 to 6 moles,preferably 3 to 5 moles per mole of the 2,4-difluorobenzoic acidderivative.

The reaction temperature used in the process of the present inventioncan be determined appropriately at a temperature not higher than theboiling point of the solvent used, but is preferably 80 to 200° C., morepreferably 100 to 160° C. The reaction time is usually about 2 to 12hours. The pressure employed during the reaction may be any ofatmospheric pressure, applied pressure or reduced pressure, butatmospheric pressure is employed usually.

The 4-fluorosalicylic acid derivative which is an intended product inthe process of the present invention, i.e. the compound of the presentinvention can be isolated by subjecting the reaction mixture after thecompletion of the reaction to an ordinary isolation method such asprecipitation by acidification and subsequent filtration, or solventextraction and subsequent concentration of extracting solvent. The4-fluorosalicylic acid derivative can also be taken out by filtering thereaction mixture after the completion of the reaction to separate thealkali metal salt of the product from the solvent and then subjectingthe salt to precipitation by acidification.

The above-obtained 4-fluorosalicylic acid derivative (the compound ofthe present invention) can be used without being purified, or can bepurified by being recrystallized from an alcohol-water mixed solvent orthe like.

(Production of 3-fluorophenol derivative)

Next is described, for reference, a process for producing, from the4-fluorosalicylic acid derivative (the compound of the presentinvention), a 3-fluorophenol derivative which is useful as anintermediate for liquid crystal, etc.

That is, the 3-fluorophenol derivative can be produced by heating the4-fluorosalicylic acid derivative of the present invention representedby the general formula (1), in the presence of a base in the presence orabsence of a solvent.

As the base, an organic base or an inorganic base can be used. As theorganic base, there can be mentioned, for example, a tertiary amine(which is a nitrogen-containing organic base free from [N]--H and whichis a tertiary amine in a broad sense); specific examples thereof arepyridines [e.g. pyridine and 4-(N,N-dimethylamino)pyridine (DMAP)],quinolines (e.g. quinoline), trialkylamines (e.g. triethylamine andtrioctylamine) and N,N-dialkylanilines (e.g. N,N-dimethylaniline). Theamount of the organic base used is 0.01 to 50 moles, preferably 0.1 to20 moles per mole of the 4-fluorosalicylic acid derivative.

As the inorganic base, there can be used a hydroxide or carbonate of analkali metal or an alkaline earth metal. Specific examples arehydroxides of alkali metals or alkaline earth metals (e.g. sodiumhydroxide, potassium hydroxide and calcium hydroxide) and carbonates ofalkali metals or alkaline earth metals (e.g. sodium carbonate, sodiumhydrogencarbonate, potassium carbonate, potassium hydrogencarbonate,calcium carbonate and barium carbonate). The amount of the inorganicbase used is 0.01 to 5 moles, preferably 0.1 to 2 moles per mole of the4-fluorosalicylic acid derivative.

As the base used in the reaction, an organic base is preferred. Use of,in particular, guinoline, trioctylamine or 4-(N,N-dimethylamino)pyridinegives a favorable result.

The reaction proceeds with no problem in a solventless state, but asolvent may be used as necessary. When a solvent is used, there can beused a solvent inert to the reaction (e.g. giving rise to no sidereaction with the 4-fluorosalicylic acid derivative), for example, anaprotic polar solvent, such as 1-methyl-2-pyrrolidone (NMP),1,3-dimethyl-2-imidazolidinone (DMI), N,N-dimethylacetamide (DMAC),tetramethylsulfone or the like.

As the solvent, there can also be used an aromatic hydrocarbon oraromatic halogenated hydrocarbon such as toluene, xylene, chlorobenzene,dichlorobenzene, trichlorobenzene or the like.

In the reaction, the above-mentioned organic base may be used so as tofunction not only as a base but also as a solvent.

In the reaction, the amount of the solvent used is, for example, 0.3 to3 litter, preferably 0.5 to 2 litter per mole of the 4-fluorosalicylicacid derivative.

The reaction temperature is in the range of, for example, 150 to 230° C.The reaction time is usually 1 to 20 hours, preferably 2 to 15 hours.The reaction may be carried out at atmospheric pressure, under appliedpressure or under reduced pressure.

The 3-fluorophenol formed in the reaction can be taken out by a methodwhich differs depending upon the solvent used in the reaction, forexample, by a method of acid-washing the reaction mixture, separatingthe resulting organic layer and then subjecting the separated organiclayer to concentration or rectification, or by a method of subjectingthe reaction mixture to precipitation by acidification and subsequentsolvent extraction and then subjecting the resulting organic layer toconcentration or rectification.

The present invention is described more specifically below by way ofExamples and Reference Examples.

EXAMPLE 1

1.76 g (0.01 mole) of 2,3,4-trifluorobenzoic acid, 1.62 g (0.04 mole) ofpowdery 99% sodium hydroxide and 20 ml of 1,3-dimethyl-2-imidazolidinonewere fed into a 100-ml four-necked flask provided with a thermometer, astirrer and a reflux condenser. The mixture was stirred at 150° C. for 2hours to give rise to a reaction. After the completion of the reaction,part of 1,3-dimethyl-2-imidazolidinone was recovered. The resultingreaction mixture was diluted with 500 ml of water and then subjected toprecipitation with a 10% aqueous hydrochloric acid solution. Theresulting material was cooled in an ice bath. The resulting crystalswere collected by filtration, washed with water, and dried to obtain1.66 g of 3,4-difluorosalicylic acid. The isolated yield was 95.1%relative to the 2,3,4-trifluorobenzoic acid used.

(Properties of 3,4-difluorosalicylic acid)

Melting point: 176.8 to 178.2° C.

(Confirmation data)

MS m/z: 174 (M⁺)

60 MHz ¹ H-NMR (DMSO-d₆ +CDCl₃) δ value: 6.63-7.20 (m, 1H), 7.47-7.90(m, 1H), 8.33 (brs, 2H)

IR (KBr tablet, cm⁻¹): 3431, 3211, 3104, 3079, 3022, 2942, 2864, 2677,2546, 2343, 1658, 1573, 1540, 1512, 1470, 1445, 1384, 1316, 1277, 1214,1200, 1149, 1054, 909, 831, 785, 716, 689, 609

EXAMPLE 2

1.93 g (0.01 mole) of 5-chloro-2,4-difluorobenzoic acid, 1.62 g (0.04mole) of powdery 99% sodium hydroxide and 20 ml of1-methyl-2-pyrrolidone were fed into a 100-ml four-necked flask providedwith a thermometer, a stirrer and a reflux condenser. The mixture wasstirred at 130° C. for 3 hours to give rise to a reaction. After thecompletion of the reaction, part of 1-methyl-2-pyrrolidone wasrecovered. The resulting reaction mixture was diluted with 500 ml ofwater and then subjected to precipitation with a 10% aqueoushydrochloric acid solution. The resulting crystals were collected byfiltration, washed with water, and dried to obtain 1.76 g of5-chloro-4-fluorosalicylic acid. The isolated yield was 92.1% relativeto the 5-chloro-2,4-difluorobenzoic acid used.

(Properties of 5-chloro-4-fluorosalicylic acid)

Melting point: 200.0 to 201.2° C.

(Confirmation data)

MS m/z: 190 (M⁺)

60 MHz ¹ H-NMR (DMSO-d₆ +CDCl₃) δ value: 6.79 (d, 1H, J=10.3 Hz), 7.92(d, 1H, J=8.8 Hz), 9.46 (brs, 2H)

IR (KBr tablet, cm⁻¹): 3630-3280, 1669, 1616, 1590, 1491, 1475, 1449,1377, 1276, 1248, 1212, 1166, 849, 703, 611

EXAMPLE 3

2.27 g (0.01 mole) of 3,5-dichloro-2,4-difluorobenzoic acid, 1.62 g(0.04 mole) of powdery 99% sodium hydroxide and 20 ml of1-methyl-2-pyrrolidone were fed into a 100-ml four-necked flask providedwith a thermometer, a stirrer and a reflux condenser. The mixture wasstirred at 130° C. for 2 hours to give rise to a reaction. Then, thesame post-treatment as in Example 2 was conducted to obtain 2.07 g of3,5-dichloro-4-fluorosalicylic acid. The isolated yield was 91.4%relative to the 3,5-dichloro-2,4-difluorobenzoic acid used.

(Properties of 3,5-dichloro-4-fluorosalicylic acid)

Melting point: 119.4 to 120.9° C.

(Confirmation data)

MS m/z: 225 (M⁺)

60 MHz ¹ H-NMR (DMSO-d₆ +CDCl₃) δ value: 7.39 (brs, 2H), 7.89 (d, 1H,J=8.2 Hz)

IR (KBr tablet, cm⁻¹): 3451, 3428, 1674, 1641, 1607, 1545, 1474, 1458,1432, 1307, 1292, 1241, 1057, 810, 720, 659

EXAMPLE 4

1.76 g (0.01 mole) of 2,4,6-trifluorobenzoic acid, 1.62 g (0.04 mole) ofpowdery 99% sodium hydroxide and 20 ml of 1-methyl-2-pyrrolidone werefed into a 100-ml four-necked flask provided with a thermometer, astirrer and a reflux condenser. The mixture was stirred at 130° C. for 3hours to give rise to a reaction. Then, the same post-treatment as inExample 2 was conducted to obtain 1.47 g of 4,6-difluorosalicylic acid.The isolated yield was 84.3% relative to the 2,4,6-trifluorobenzoic acidused.

(Properties of 4,6-difluorosalicylic acid)

Melting point: 180.8 to 183.4° C.

(Confirmation data)

MS m/z: 174 (M⁺)

60 MHz ¹ H-NMR (DMSO-d₆ +CDCl₃) δ value: 6.27-6.80 (m, 2H), 7.20 (brs,2H)

IR (KBr tablet, cm⁻¹): 3421, 3274, 3106, 3005, 2964, 2929, 1667, 1632,1598, 1561, 1509, 1465, 1436, 1365, 1325, 1253, 1178, 1137, 1065, 854,830, 787, 612

EXAMPLE 5

3.88 g (0.02 mole) of 2,3,4,5-tetrafluorobenzoic acid, 3.23 g (0.08mole) of powdery 99% sodium hydroxide and 40 ml of1,3-dimethyl-2-imidazolidinone were fed into a 200-ml four-necked flaskprovided with a thermometer, a stirrer and a reflux condenser. Themixture was stirred at 130° C. for 3 hours to give rise to a reaction.Then, the same post-treatment as in Example 1 was conducted to obtain1.14 g of 3,4,5-trifluorosalicylic acid. The isolated yield was 29.7%relative to the 2,3,4,5-tetrafluorobenzoic acid used.

(Properties of 3,4,5-trifluorosalicylic acid)

Melting point: 75.0 to 76.8° C.

(Confirmation data)

MS m/z: 192 (M⁺)

60 MHz ¹ H-NMR (DMSO-d₆ +CDCl₃) δ value: 7.27-7.73 (m, 1H), 8.72 (brs,2H)

IR (KBr tablet, cm⁻¹): 2885, 1687, 1650, 1614, 1526, 1465, 1285, 1232,1032, 905, 775, 694.

EXAMPLE 6

1.76 g (0.01 mole) of 2,4,5-trifluorobenzoic acid, 1.62 g (0.04 mole) ofpowdery 99% sodium hydroxide and 20 ml of 1,3-dimethyl-2-imidazolidinonewere fed into a 100-ml four-necked flask provided with a thermometer, astirrer and a reflux condenser. The mixture was stirred at 130° C. for 3hours to give rise to a reaction. Then, the same post-treatment as inExample 1 was conducted to obtain 0.50 g of 4,5-difluorosalicylic acid.The isolated yield was 28.7% relative to the 2,4,5-trifluorobenzoic acidused.

(Properties of 4,5-difluorosalicylic acid)

Melting point: 134.4 to 137.0° C.

(Confirmation data)

MS m/z: 174 (M⁺)

60 MHz ¹ H-NMR (DMSO-d₆ +CDCl₃) δ value: 6.60-7.00 (m, 1H), 7.27 (brs,2H), 7.47-7.93 (m, 1H)

IR (KBr tablet, cm⁻¹): 3083, 1669, 1605, 1506, 1448, 1282, 1249, 1208,1158, 897, 861, 698, 656

REFERENCE EXAMPLES 1 TO 6

0.01 mole of a 4-fluorosalicylic acid derivative and 10 ml of quinolinewere fed into a 50-ml flask provided with a stirrer and a refluxcondenser. The mixture was stirred for 2 hours in an oil bath of 230° C.to give rise to a reaction to convert the 4-fluorosalicylic acidderivative to a 3-fluorophenol derivative. The reaction mixture wassubjected to gas chromatography and GC-MS. The results are shown inTable 1.

                                      TABLE 1                                     __________________________________________________________________________          Raw Material  Product    Purity                                           Reference (4-Fluorosalicylic (3-fluoropheno (GC total MS m/z                  Examples acid derivative) 1 derivative) area %) (M                                                              +)                                        __________________________________________________________________________      1                                                                                                                 #STR8##                                                                       96.4 130                                   - 2                                                                                                              #STR10##                                                                      96.7 130                                   - 3                                                                                                              #STR12##                                                                      96.9 130                                   - 4                                                                                                              #STR14##                                                                      96.9 148                                   - 5                                                                                                              #STR16##                                                                      94.6 146                                   - 6                                                                                                              #STR18##                                                                      99.8 180                                __________________________________________________________________________

INDUSTRIAL APPLICABILITY

The present invention provides a novel 4-fluorosalicylic acidderivative. The 4-fluorosalicylic acid derivative is very suitable as araw material for production of a 3-fluorophenol derivative which is veryuseful as an intermediate for liquid crystal, recording material,medicine and agricultural chemical.

What is claimed is:
 1. A 4-fluorosalicylic acid derivative representedby the following formula (1): ##STR20## wherein X¹, X² and X³ are eachindependently a hydrogen atom or a halogen atom with the proviso thatthere is no case in which all of X¹, X² and X³ are hydrogen atoms orfluorine atoms and with the proviso that the compound5-bromo-4-fluorosalicylic acid is excluded.
 2. A process for producing a4-fluorosalicylic acid derivative represented by the following formula(1): ##STR21## wherein X¹, X² and X³ are each independently a hydrogenatom or a halogen atom with a proviso that there is no case in which allof X¹, X² and X³ are hydrogen atoms or fluorine atoms, which processcomprises reacting a 2,4-difluorobenzoic acid derivative represented bythe formula (4): ##STR22## wherein X¹, X² and X³ are each independentlya hydrogen atom or a halogen atom with the proviso that there is no casein which all of X¹, X² and X³ are hydrogen atoms or fluorine atoms, withan alkali metal hydroxide in at least one solvent selected from thegroup consisting of a compound represented by the following formula (2):##STR23## wherein A is a group --CH₂ -- or a group --NR'--, wherein R'is a lower alkyl group; R is a lower alkyl group; W is a lower alkylgroup; X is hydrogen atom or a lower alkyl group when A is a group --CH₂--, and is a lower alkyl group when A is a group --NR'--; W and X maycombine with each other to form a lower alkylene group and become a 5-to 7-membered ring together with --N--C--A--, and a compound representedby the following formula (3):

    Y--Q--Z                                                    (3)

wherein Q is a group --SO-- or a group --SO₂ --; Y and Z are eachindependently a lower alkyl group; Y and Z may combine with each otherto form a lower alkylene group and become a 4- to 6-membered ringtogether with a group --SO-- or a group --SO₂ --.